It was previously shown that carvedilol, a beta-adrenergic receptor antagonist with antioxidant properties, was able to inhibit the mitochondrial permeability transition (MPT). In the present work, the hypothesis was that the negative impact of carvedilol on the MPT was specifically the result of its antioxidant effect. For the current investigation, we used three different MPT inducers. MPT-associated events were tested to study the protective effect of both carvedilol and cyclosporin-A, the known MPT inhibitor. Carvedilol inhibited mitochondrial swelling with calcium plus phosphate and with calcium plus t-butylhydroperoxide, but not with calcium plus carboxyatractyloside. Carvedilol inhibited the oxidation of thiol groups with calcium plus phosphate (p < 0.01) and with calcium plus t-butylhydroperoxide (p < 0.05), but not with calcium plus carboxyatractyloside--in opposition to the full protection afforded by cyclosporin-A when using calcium and carboxyatractyloside. Our results showed that carvedilol was effective only when the MPT was triggered by a primary oxidative process. This finding implies that the antioxidant properties of carvedilol are crucial for the observed effects and reinforces the advantageous use of carvedilol in cardiac pathologies associated with enhanced cellular oxidative stress.